tbuckley/cabot-search huggingface dataset:
P1173: CLINICAL APPLICABILITY OF TARGETED NEXT-GENERATION SEQUENCING FOR PRECISION MEDICINE IN DIFFUSE LARGE B CELL LYMPHOMA
Authors: D. Huang, J. Li, T. Yang, Y. Nan, L. Zhang, Y. Xiang, Q. Li, Y. Liu
Journal: HemaSphere (2022)

Background: The cure rate of diffuse large B-cell lymphoma is only 60-70%, and new treatment methods need to be found. Aims: Comprehensive genomic analysis based on next-generation sequencing (NGS) allows a better molecular characterization of diffuse large B-cell lymphoma, offering a roadmap toward precision medicine. Methods: We analyzed somatic alterations of 37 DLBCL tissue or blood samples by a hybridization capture-based NGS panel targeting 188 lymphoma-related genes. Results: Totally, 279 single-nucleotide variants and small insertions or deletions affecting 103 genes were identified, with at least 1 mutation detected in 100% (37/37) of cases. The most frequently mutated genes were those involved in epigenetic modifiers (DNMT3A, KMT2B and KMT2D), activated signaling (TYK2, MYD88, NOTCH2 and BCR) and transcription factors/transcriptional regulator (RUNX1, SPEN, IRF4, KLF2 and ASXL1). Significant co-occurrences were shown between RUNX1 mutations with NOTCH2, IRF4, ARID1A and BCR (P<0.05, respectively), BCR and IRF4 (P<0.01), etc. Additionally, we analyzed the association of genomic aberrations with clinicopathological features in DLBCL. Patients aged >60 years harbored less LRP1B mutations than those aged ≤60 years (5.3% vs. 33.3%, P< 0.05). The mutation frequency of TP53 was significantly higher in LDH-high (>244 U/L) group than that in LDH-low (≤244 U/L) group (40% vs. 6.25%, P<0.05). Compared with germinal center B-cell (GCB), the mutation frequency of TYK was significantly lower in non-GCB (5% vs. 36.4%, P<0.05). New potential therapeutic targets (CREBBP, EP300, EZH2, SMARCB1, CD79A/B, BTK, CARD11, MYD88, THFAIP3, PIK3CA, PTEN and JAK) were identified in 55% (11/20) of newly diagnosed patients and in 41.2% (7/17) of relapsed/refractory patients. Ibrutinib, as a single agent, has demonstrated limited activity in DLBCL with mutant MYD88 and wildtype CD79. In this study, we identified 3 patients with mutant MYD88 and wildtype CD79A/B (8.1%), among whom 2 harbored MYD88 L265P variants and 1 had MYD88 S219C mutation. Summary/Conclusion: The utility of mutational profiling may facilitate the identification of potential drug targets, which in turns may represent new therapeutic possibilities.
Abstract LB127: Reduced expression of annexin-a6 induces metabolic reprogramming that favors rapid fatty acid oxidation in triple-negative breast cancer cells
Authors: Stephen D. Williams, Sarrah E. Widatalla, Amos M. Sakwe
Journal: Cancer Research (2022)

Abstract The ability of cancer cells to alter their metabolism is one of the major mechanisms underlying rapid tumor progression and/or therapeutic resistance in solid tumors, including the hard-to-treat triple-negative breast cancer (TNBC) subtype. Here, we assessed the contribution of the tumor suppressor, Annexin A6 (AnxA6) in the metabolic adaptation of rapidly growing versus invasive TNBC cells as well as in Lapatinib resistant (Lap-R) TNBC cells. AnxA6 expression in cultured TNBC cell lines, Lap-R cells and in crude isolates of mitochondria was determined by Western blotting and/or immunofluorescence assays. The oxygen consumption rates (OCR), extracellular acidification rates (ECAR) and mitochondria activity were assessed using the Seahorse XF Analyzer. Intracellular metabolites were detected by 1H-NMR analysis. Using model proliferative basal-like and invasive mesenchymal-like TNBC cell lines, we show that TNBC cells also exhibit metabolic heterogeneity. Down regulation of AnxA6 in TNBC cells attenuated mitochondrial respiration, glycolytic flux, and cellular ATP production capacity, resulting in a quiescent cellular energy phenotype. We further show that AnxA6-depletion was associated with decreased lipid droplet accumulation and the lipolytic phenotype by enhancing the uptake and mitochondrial fatty acid oxidation for ATP production. Chronic Lapatinib-induced up regulation of AnxA6 in AnxA6-low TNBC cells reversed their lipolytic to a more lipogenic/glycolytic metabolic phenotype with gluconeogenic precursors as additional metabolites. Collectively, these data suggest that the expression status of AnxA6 in TNBC cells underlies significant metabolic adaptation during stress and/or chronic Lapatinib treatment and provide additional insights into the potential of AnxA6 as a biomarker for not only therapeutic intervention but also the metabolic subtyping of TNBC subsets. Citation Format: Stephen D. Williams, Sarrah E. Widatalla, Amos M. Sakwe. Reduced expression of annexin-a6 induces metabolic reprogramming that favors rapid fatty acid oxidation in triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB127.
PB1858: INFLUENCE OF INFLAMMATION ON ANGIOGENIC FACTORS IN CHRONIC LYMPHOCYTIC LEUKEMIA
Authors: O. Mitrović Ajtić, T. Subotički, M. Diklić, D. Đikić, M. Vukotić, T. Dragojević, E. Živković, D. Antić, V. Čokić
Journal: HemaSphere (2022)

Background: Several studies have shown that angiogenic factors are increased in patients with chronic lymphocytic leukemia (CLL). B-CLL cells secrete high levels of major angiogenic factors, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor, and hypoxia inducible factor 1 alpha (HIF1α). However, it remains unclear how these angiogenic factors are self-controlled during inflammation. Aims: The aim of the study is to assess the role of inflammation in activation of endothelial nitric oxide synthase (eNOS), HIF1α and VEGF angiogenic factors via proliferation related signaling pathways and VEGF self-control by negative feedback. Methods: We isolated mononuclear cells (MNC) and CD19+ cells from peripheral blood of 60 patients with CLL. MNC were treated with pro-inflammatory Interleukin-6 (IL-6) and VEGF, in combination with inhibitors of JAK1/2 (Ruxolitinib), mTOR (Rapamycin), NF-kβ (JSH23), SMAD (LDN-193189) and PI3K/AKT (Ly294002) signaling pathways, to evaluate eNOS, VEGF and HIF1α expression by immunoblotting, immunocytochemistry and RT-qPCR. Results: The angiogenic factors eNOS, VEGF and HIF1α have significantly higher frequencies in MNC of CLL in comparison to healthy controls (p<0.001), while they were reduced in CD19+ immunoreactive cells compared to MNC. IL-6 increased the quantity of HIF1α (p<0.05), while IL-6 increased the number of VEGF immunoreactive cells in the presence of JSH23 (p<0.01). HIF1α gene expression was significantly increased by VEGF (p<0.05), while eNOS gene expression was significantly decreased after VEGF and/or IL6 treatment (p<0.01) in MNC of CLL. VEGF stimulation of eNOS protein expression was prevented by inhibition of JAK1/2 and mTOR signaling in MNC of CLL (p<0.05). Immunocytochemistry revealed that VEGF significantly (p<0.001) increased the number of HIF1α positive MNC of CLL. Treatment with RUXO, Ly294002 and Rapamycin significantly decreased the number of HIF1α and eNOS immunoreactive cells compared to control and VEGF treated MNC of CLL (p<0.001). VEGF stimulated activation of SMAD (p<0.05) and STAT5 (p<0.01) signaling, prevented by Ruxolitinib and Rapamycin (p<0.01) in MNC of CLL. In addition, VEGF activation of STAT5 and SMAD signaling were prevented by Ly294002 and LDN-193189, respectively (p<0.01). Summary/Conclusion: We demonstrated increased level of angiogenic factors in CLL, while pro-inflammatory IL-6 and angiogenic VEGF preferentially stimulated HIF1α. Further studies with clinical data of CLL patients will indicate their potential role in diagnosis, progression, and response to therapy.
PB2338: QUALITY OF LIFE AFTER ALLOGENIC HEMATOPOIETIC STEM CELL TRANSPLANTATION: IMPACT OF CHRONIC GVHD
Authors: D. Belloumi, R. Ouerghi, N. Ben Abdeljelil, S. Mekni, L. Torjemane, I. Turki, S. Ladeb, T. Ben Othman
Journal: HemaSphere (2022)

Background: Hematopoietic Stem Cell transplantation (HSCT) is a potentially curative treatment for several hematological diseases, but it is often complicated by significant morbidity and mortality. This is particularly related to chronic Graft versus Host Disease (GVHD) that can deeply impact patients’ quality of life (QoL). Aims: Our purpose was to evaluate patients’QoL after HSCT and to clarify the impact of chronic GVHD. Methods: We conducted a cross-sectional descriptive study at the National Bone Marrow Transplant Center including patients who underwent HSCT between January 2018 and December 2019. These patients filled in the questionnaire for the quantitative measurement of quality of life using 36-Item Short-Form Health Survey (SF-36) and to the Functional Assessement of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) during a phone interview. Results: Of the 52 patients still alive at the time of the survey, 43 patients were contactable and willing to participate (participation rate: 83%). The median age of the participants was 28 years (7-52) with a sex ratio of 1.52. Underlying disease was acute leukemia for 29 patients and aplastic anemia for 14 others. The median time between HSCT and the interview was of 26 months (17-39). At the time of the survey, all patients were in complete remission and 28% among them (12 of 43) had active extensive chronic GVHD. Results obtained in the different dimensions of the SF-36 and FACT-BMT scales indicated good overall QoL in patients after HSCT. However, using SF-36, patients with chronic active GVHD had significantly lower scores on « role limitation due to their physical condition » (p=0.001), «role limitation due to their psychological condition » (p=0.0001), « vitality » (p= 0.045) and « general health perception » (p=0.027) than the other patients. In addition, the FACT-BMT score revealed a negative impact on chronic GVHD in physical well-being dimension (p=0.009) and the functional well-being dimension (p=0.027). Apart from chronic active GVHD, a negative impact on QoL was noted with: adult age, peripheral stem cells transplants and GVHD prophylaxis with ciclosporin alone. Summary/Conclusion: Active chronic GVHD was associated with impared QoL in patients after HSCT hence the need for rapid diagnosis and optimal prophylaxis and treatment of this complication.
P1689: TISSUE-SELECTIVE PHARMACOLOGICAL TARGETING OF TUMOR INTRINSIC PROTHROMBIN (F2) EXPRESSION USING AN INTEGRATED GENETIC REPORTER SYSTEM
Authors: E. Khan, J. Nourse, S. Tokalov, S. Khokhar, D. Arnold-Schild, L. Schott, L. Eder, S. Danckwardt
Journal: HemaSphere (2022)

Background: Thrombin is the central protease involved in blood coagulation. Beyond its well-established role in stemming blood loss, it has a detrimental function in various (patho)physiological conditions including sepsis and various cancers. Around 17 million deaths occur worldwide due to cancer annually and blood coagulation, specifically thrombin, has been shown to play an important role. Prothrombin (F2), the precursor of thrombin is primarily synthesized in the liver. Aims: To decipher and target tissue-selective pharmacological targeting of tumor intrinsic F2 expression using an integrated genetic reporter system Methods: By using an innovative newly generated knock-in reporter mouse model combined with non-invasive molecular imaging, extra-hepatic expression of F2 in tumors was discovered, recapitulating findings in cancer patients. Results: Strikingly, tumor-intrinsic F2 not only contributes to a thrombophilic state, it also exerts a protumorigenic function. We next set out to define modalities to selectively interfere with tumor-derived F2 without altering the natural source of hemostatic F2 production (i.e., in the liver). In a pilot screening using syngenic reporter lines, we identified pathways that allow selective pharmacological targeting of tumor-derived F2. Summary/Conclusion: This confirms the in principle selective druggability of gene expression of this central serine protease in a target-tissue specific manner. It thereby opens potentially new therapeutic avenues to interfere with detrimental tumor-intrinsic F2 expression without impairing the normal hemostatic function of liver-derived prothrombin.
Poziotinib Inhibits HER2-Mutant–Driven Therapeutic Resistance and Multiorgan Metastasis in Breast Cancer
Authors: Rashi Kalra, Ching Hui Chen, Junkai Wang, Ahmad Bin Salam, Lacey E. Dobrolecki, Alaina Lewis, Christina Sallas, Clayton C. Yates, Carolina Gutierrez, Balasubramanyam Karanam, Meenakshi Anurag, Bora Lim, Matthew J. Ellis, Shyam M. Kavuri
Journal: Cancer Research (2022)

The pan-HER tyrosine kinase inhibitor (TKI) neratinib is therapeutically active against metastatic breast cancers harboring activating HER2 mutations, but responses are variable and often not durable. Here we demonstrate that recurrent HER2 mutations have differential effects on endocrine therapy responsiveness, metastasis, and pan-HER TKI therapeutic sensitivity. The prevalence and prognostic significance may also depend on whether the HER2 mutant has arisen in the context of lobular versus ductal histology. The most highly recurrent HER2 mutant, L755S, was particularly resistant to neratinib but sensitive to the pan-HER TKI poziotinib, alone or in combination with fulvestrant. Poziotinib reduced tumor growth, diminished multiorgan metastasis, and inhibited mTOR activation more effectively than neratinib. Similar therapeutic effects of poziotinib were observed in both an engineered HER2L755S MCF7 model and a patient-derived xenograft harboring a HER2G778_P780dup mutation. Overall, these findings support the need for clinical evaluation of poziotinib for the treatment of HER2-mutant metastatic breast cancer.Evaluation of the functional impact of HER2 mutations on therapy-induced resistance and metastasis identifies robust antitumor activity of poziotinib and supports the clinical evaluation of poziotinib in ER+ HER2 mutant breast cancer.
PB2056: MYELOFIBROSIS IN PATIENTS OLDER THAN 70 YEARS: IS TREATMENT WITH RUXOLITINIB WORTH IT?
Authors: M. I. Montero
Journal: HemaSphere (2022)

Background: Myelofibrosis is an agressive myeloproliferative neoplasm with a higher incidence in older patients who have worse prognosis. In last years, ruxolitinib, a JAK1/2 inhibitor that may control myelofibrosis (MF)-related splenomegaly and symptoms, han been used in this disease regardless of age. Aims: Fifty three patients treated with ruxolitinib between April 2012 and March 2021 from a clinical database of 149 patients were studied in order to assess the effect of age in survival and toxicities Methods: Diagnosis of primary MF (PMF) an post-Essential Thrombocytemia /post-Polycithemic MF was made according to the WHO 2016. Molecular tests for detection for JAK2, MPL and CALR mutations were performed. Ruxolitinib starting dose was decided accordingly to prescribing information.Survival analysis was performed by means of Kaplan-Meier curves and differences between KM curves were evaluated using the Log-rank test. P values less than 0.05 were considered satistically significant. Analyses were performed with SPSS software v.15. Results: Median age was 64 years (range 36–88); median haemoglobin was 110 g/l (range, 60–157) and 48,1% patients had a transfusion-dependent anemia. Median platelet an leucocyte counts were respectively 311 × 109/l (range, 52–1887) and 14,8 × 109/l (range, 52–1887). 54,5% patients have a PMF diagnosis. JAK2V617F was present in 69,8% patients, CALR mutations in 15,4% and MPLW515K/L in 5,3%; 9,5%of the patients were triple negatives. Leucocytes <15x10e9/ and JAK2V617F were correlated with better survival. At the moment of diagnosis, 32,7% of patients were older than 70 years. In this group, the median of survival from the diagnosis was 70 months. Causes of death were, specifically: progression of myelofibrosis (22,2%), evolution into acute leukemia (22,2%), second neoplasias (22,2%), heart disease (33,3%). Summary/Conclusion: 1.-Elderly patients in our group treated with ruxolitinib have a median survival of 70 months which is a clear advantage with respect to historic cohorts of MF. 2.-Ruxolitinib was well tolerated but does not avoid clonal evolution and JAK1 inhibition could worsen tumor inmmunosurveillance.
PB1828: CADENZA: A PIVOTAL STUDY OF PIVEKIMAB SUNIRINE (IMGN632) IN PATIENTS WITH UNTREATED/FRONTLINE BPDCN
Authors: N. Pemmaraju, G. Martinelli, E. Todisco, C. Tarella, P. Montesinos, A. A. Lane, H. P. Erba, K. L. Sweet, R. B. Walter, E. Deconinck, E. S. Wang, A. Aribi, M. L. Ulrikson, M. Y. Levy, D. Lebon, G. Marconi, D. J. DeAngelo, D. Rizzieri, M. Konopleva, C. M. Sloss, J. Wang, K. A. Malcolm, P. A. Zweidler-McKay, N. G. Daver
Journal: HemaSphere (2022)

Background: Overexpression of CD123 occurs in multiple hematological malignancies, including blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and others. With limited expression on normal hematopoietic progenitor cells, the CD123 antigen is an attractive target for new therapeutics. IMGN632 is a CD123-targeting antibody-drug conjugate (ADC) comprising a novel anti-CD123 antibody coupled, via a peptide linker, to a unique DNA-alkylating cytotoxic payload of the IGN (indolinobenzodiazepine pseudodimer) class. Preclinically, IMGN632 has demonstrated potent activity against BPDCN, AML, and ALL models, with a wide therapeutic index in animal models, as well as 150-fold differential cytotoxicity in AML patient-derived samples compared to normal hematopoietic progenitors (Kovtun. Blood Adv (2018) 2(8):848, Angelova. Haematologica (2019) 104(4):749). In particular, remarkable sensitivity of BPDCN patient-derived xenografts to IMGN632 was demonstrated (Zhang Blood (2018) 132:3956). The clinical safety profile of IMGN632 in BPDCN is characterized by low-grade peripheral edema and infusion reactions, and reversible veno-occlusive disease in < 5%; there have been no capillary leak syndrome and no treatment-related deaths. Data in relapsed or refractory BPDCN led to FDA granting of Breakthrough Therapy Designation for IMGN632 (October 2020). We have previously reported three of three frontline BPDCN patients achieved clinical complete responses (CRc) with duration of response (DOR) of up to 10.7 months without transplant (Pemmaraju. ASH 2021 Abstract #1284). Aims: This study is designed to determine the safety, tolerability, and activity of IMGN632 when administered to patients with frontline BPDCN. Methods: The dose escalation phase identified a recommended phase 2 dose of 0.045 mg/kg given intravenously every 3 weeks. Expansion cohorts include a pivotal cohort for frontline/untreated BPDCN (no prior systemic therapy), and exploratory cohorts for patients with relapsed or refractory BPDCN. Patients with central nervous system disease are not eligible in the frontline BPDCN cohort. Results: N/A Summary/Conclusion: Enrollment continues in the pivotal cohort for frontline/untreated BPDCN patients. CADENZA, https://BPDCNtrial.com, NCT03386513
Novel cancer gene discovery using a forward genetic screen in RCAS-PDGFB-driven gliomas
Authors: Holger Weishaupt, Matko Čančer, Gabriela Rosén, Karl O Holmberg, Susana Häggqvist, Ignas Bunikis, Yiwen Jiang, Smitha Sreedharan, Ulf Gyllensten, Oren J Becher, Lene Uhrbom, Adam Ameur, Fredrik J Swartling
Journal: Neuro-Oncology (2022)

Abstract Background Malignant gliomas, the most common malignant brain tumors in adults, represent a heterogeneous group of diseases with poor prognosis. Retroviruses can cause permanent genetic alterations that modify genes close to the viral integration site. Methods Here we describe the use of a high-throughput pipeline coupled to the commonly used tissue-specific retroviral RCAS-TVA mouse tumor model system. Utilizing next-generation sequencing, we show that retroviral integration sites can be reproducibly detected in malignant stem cell lines generated from RCAS-PDGFB-driven glioma biopsies. Results A large fraction of common integration sites contained genes that have been dysregulated or misexpressed in glioma. Others overlapped with loci identified in previous glioma-related forward genetic screens, but several novel putative cancer-causing genes were also found. Integrating retroviral tagging and clinical data, Ppfibp1 was highlighted as a frequently tagged novel glioma-causing gene. Retroviral integrations into the locus resulted in Ppfibp1 upregulation, and Ppfibp1-tagged cells generated tumors with shorter latency on orthotopic transplantation. In human gliomas, increased PPFIBP1 expression was significantly linked to poor prognosis and PDGF treatment resistance. Conclusions Altogether, the current study has demonstrated a novel approach to tagging glioma genes via forward genetics, validating previous results, and identifying PPFIBP1 as a putative oncogene in gliomagenesis.
P1400: BOOSTING MITOCHONDRIAL RECYCLING REJUVENATES HEMATOPOIETIC AND IMMUNE SYSTEMS
Authors: Y.-H. Chiang, M. Girotra, M. Charmoy, H. Carrasco Hope, P. Ginefra, F. Schyrr, F. Franco, P.-C. Ho, O. Naveiras, J. Auwerx, W. Held, N. Vannini
Journal: HemaSphere (2022)

Background: Hematopoietic stem cells (HSCs) generate all blood lineages and ensure the correct homeostasis between myeloid and lymphoid lineages during the entire life of an organism. However, HSCs decrease their regenerative potential and undergo toward a myeloid-biased fate skewing with age. This phenomenon leads to a reduction of B and T cell compartments and immune dysfunction. Consequently, elderly patients are more susceptible to severe viral and fungal infections. It was reported that HSC aging is associated with defective autophagy and accumulation of damaged mitochondria. And emerging studies showed that dysregulation of mitochondria metabolism correlates closely with hematopoietic aging process. However, the clear causal relationship between mitochondrial metabolism and HSC aging remains unknown. Aims: We were wondering if metabolic modulator can rejuvenate aged HSCs, rescue loss-of-function of aged HSCs and improve overall immune response. Methods: We used mito-QC reporter mice and mitochondrial stain to analyze mitochondrial network upon in vitro treatment of metabolic modulator. In vivo long-term blood reconstitution assays and LCMV infection model were used to estimate the effect of metabolic modulator on HSC functionality. Results: Here we reported that interventions aimed to modulate mitochondria recycling and metabolism can rejuvenate aged HSCs and thus preserving the lymphoid compartments and immune function. In vitro administration of the mitophagy inducer Urolithin A on aged HSCs restore their blood and immune reconstitution capability. Moreover, Urolithin A supplemented in the mouse diet, improves bone marrow functionality, expands the lymphoid compartment and boost immune response against viral infection in old mice. Finally, we discovered that HSCs rejuvenation is associated with mitophagy induction and re-establishment of mitochondria homeostasis and fitness in aged HSCs. Summary/Conclusion: In summary, we identified mitophagy as potent regulator of aging process and as valuable target for rejuvenating approaches in HSCs.
Differences in Cerebral Blood Flow in Gliomas on Magnetic Resonance Imaging Scanners with Magnetic Field Strengths of 1.5 and 3 T by the Method of Pseudo-Continuous Non-Contrast Perfusion
Authors: A. V. Sudarikova, A. I. Batalov, E. L. Pogosbekyan, L. M. Fadeeva, N. E. Zakharova, I. N. Pronin
Journal: Radiology - Practice (2022)

The aim of this work is to evaluate the universality of non-contrast MR perfusion (PCASL) in determining the rate of cerebral blood flow (CBF) of brain gliomas using magnetic resonance scanners with different magnetic field strengths. The maximum and normalized CBF values, which received on 1.5 and 3.0 T MRI in the same patients with histologically verified high grade gliomas (III, IV grade), were compared with each other. The data obtained by us are reliably comparable, which allows us to consider pCASL as a universal technique for scanners with different magnetic strengths.